Urokinase: a chemotactic factor for polymorphonuclear leukocytes in vivo

Area of Science:

• Immunology
• Inflammation research
• Biochemistry

Background:

• Urokinase is a serine protease with known biological activities.
• Chemotaxis, the directed movement of cells, is crucial for immune responses.
• Complement component 5a (C5a) is a known chemoattractant.

Purpose of the Study:

• To investigate the chemotactic effects of urokinase in mice.
• To determine the role of enzyme activity and C5a in urokinase-induced chemotaxis.
• To explore the phenomenon of urokinase-induced desensitization and its specificity.

Main Methods:

• Subdermal air sacs were created on the backs of mice.
• Various concentrations of urokinase were injected into the air sacs.
• Systemic desensitization was induced by intraperitoneal injection of urokinase.
• Chemotactic responses were assessed by measuring cellular infiltration.
• Responses to other chemoattractants (f-met-leu-phe, C5a, NGF, thrombin, plasmin, factor X activating enzyme) were tested in desensitized and non-desensitized mice.

Main Results:

• Urokinase demonstrated chemotactic activity in a specific concentration range (2 X 10(-13) to 2 X 10(-15) M).
• The chemotactic effect was dependent on urokinase's serine esterase activity but independent of C5a generation.
• High urokinase doses (> 2 X 10(-12) M) inhibited cellular infiltration.
• Systemic urokinase administration led to desensitization, specifically blocking subsequent urokinase-induced chemotaxis.
• Desensitization did not affect responses to f-met-leu-phe or C5a-dependent stimuli, but blocked responses to nerve growth factor, thrombin, plasmin, and factor X activating enzyme.

Conclusions:

• Three distinct inflammatory pathways exist in mice: C5-independent/urokinase-insensitive, C5-independent/urokinase-sensitive, and C5-dependent/urokinase-insensitive.
• Urokinase-induced desensitization reveals a specific inflammatory pathway that can be modulated by urokinase.
• The findings highlight the complex regulation of inflammatory cell recruitment and the potential for targeted therapeutic interventions.